Human immunodeficiency virus (HIV-1) is the etiologic agent of acquired immunodeficiency syndromes (AIDS). The HIV-1 envelope glycoproteins, gp120 and gp41, play critical roles during virus entry into the target cell, mediating binding to the CD4 receptor and the fusion of viral and cellular membranes. The location of the envelope glycoproteins outside of the viral membrane renders these molecules important targets for therapeutic and vaccine development, since they are the only viral components accessible to antibodies. Recent estimates of the short half-life of HIV-1-producing cells suggest the probable importance of viral cytopathic effect, which is mediated by the viral envelope glycoproteins, to CD4 depletion in vivo. The goal of the proposed work is to understand the structure-function relationships of the HIV-1 envelope glycoproteins important for membrane fusion, a process that contributes to virus entry and cytopathic effect. The specific aims of the proposal are: 1) to understand the structural requirements in the CD4 receptor and the HIV-1 envelope glycoproteins for triggering fusion-related conformational changes; 2) to characterize the functional interactions involving the major gp120 variable loops in the fusion process; and 3) to define the molecular determinants of the acute cytopathic effect of HIV-1 (ie., single cell lysis).